Gene gold turning to dust?

Governments are sinking further billions into genomics and related research but a new study finds no sign of revolution in healthcare.

• No Biotech Revolution in Sight
• Biotech Wonder Tool in Disarray
• Gene Therapy Woes
• Controversy over Gene Therapy ‘Breakthrough’
• Why Genomics Won't Deliver

ISIS Report 12/04/05

Why Genomics Won’t Deliver

Dr. Mae-Wan Ho called the human genome a "big white elephant" when it was first announced. It is indeed turning out to be a useless idol robbing the public of investments that can really deliver health to the nation equitably and effectively

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The new eugenics

"We propose that the IQs of the populations are one of the principle but hitherto unrecognised reasons why some countries are rich and others poor….

"…we believe it is likely that the difference in IQs between nations have a substantial genetic basis."

In their book, IQ & the Wealth of Nations, Richard Lynn, emeritus professor of psychology in University of Ulster, and Tatu Vanhanen, emeritus professor of political science in the University of Finland (also father of Finland’s current Prime Minister who has distanced himself from such ideas), took the two most dubious and controversial measures - IQ for intelligence and GDP for wealth of the nation - saw a rough correlation between the two, and claimed that the level of intelligence is responsible for how rich or poor the country is, and further, that intelligence is genetically determined.

In one bold stroke, they claim to have solved "the riddle of why some countries are rich and others are so poor."

The book was widely publicised in the UK. The Times carried an article on it, and BBC Radio 4 interviewed the Irish author twice on successive days.

According to Lynn and Vanhanen, there are four groups of countries as far as IQ scores are concerned. The highest scores, averaging 105, belong to the Oriental peoples of the Pacific rim – Japan, South Korea, Taiwan, China, Hong Kong and Singapore; the Europeans in Europe, the United States, Canada, Australia, and New Zealand average around 100; the natives of south Asia, north Africa and most Latin American countries, average around 85; the peoples in sub-Saharan Africa and the Caribbean average lowerst around 70.

In the UK, an IQ measure of 70 would put people within the lowest 2.5% of the population, who will require special needs in education. So what can an estimated average IQ of 63 for Ethiopia possibly mean but sheer nonsense at worst, and at best, that the culture in that country is most different from Europe, and that IQ tests are well known to be culturally and class-biased, and notoriously unreliable for measuring intelligence.

Intelligence, anywhere in the world in any group, is not a quantity you can grade on a single scale. It is a diverse and multifaceted faculty.

The wealth of nations, similarly, is poorly correlated with GDP. Building prisons, waging wars, litigations over divorces, breaches of safety and environmental protection all contribute a great deal to the GDP but not at all to the wealth of the nation, and certainly not to its well being.

Publicity for this book came on the back of the 50th anniversary celebration of the discovery of the double-helix of DNA in 2003, in which James Watson, who shared a Nobel Prize with Francis Crick and Maurice Wilkins (both recently deceased), was jetted many times across the oceans to give public lectures.

"If you really are stupid, I would call that a disease. The lower 10 percent who really have difficulty, even in elementary school – what’s the cause of it?" Watson was reported to have said, "A lot of people would like to say, ‘Well, poverty, things like that.’ It probably isn’t. So I’d like to get rid of that, to help the lower 10 percent."

There are two ways to ‘help’ the lower 10 percent, either by preventing them from being born, if one could identify the ‘bad’ genes that cause ‘stupidity’, or give them ‘gene therapy’ or ‘genetic enhancement’, replacing the ‘stupidity genes’ with ‘intelligent genes’; neither of which has any scientific basis whatsoever. But Watson is echoed by a coterie of ‘bio-ethicists’ and genetic engineers selling these fantasies as a subtle form of propaganda to capture further funding and investment for genomics research.

Lynn and Vanhanen were riding on the new wave of eugenics that the human genome project and the science of genomics – the study and use of genomic information - are threatening to deliver. Genomics also promises personalized medicine depending on our individual genetic makeup.

But because genomics has been privatised through gene patenting and proprietary databases, only the rich will get the benefit if any, while the poor and disadvantaged will bear the brunt of genetic discrimination from mandatory testing for health insurance and employment, and worse, pre-implantation embryo selection or prenatal testing for genetic defects so the ‘unfit’ can be eliminated before birth.

Fortunately, neither the threat nor the promise will be fulfilled, and that’s where paying attention to science is so important, the content of science as well as its social context.

Eugenics & the myth of genetic determinism

Eugenics is closed aligned with genetic determinism, the idea that organisms are hardwired in their genes. Genetic determinism is one of the most persistent dogmas in western science, and has little more substance than its forerunner, the folklore that ‘blood line’ determines destiny; which has provided the ideological backdrop to racism, racial discrimination and violence against generations of indigenous peoples, blacks, Asians, Jews and other socially and politically dispossessed groups.

James Watson sold the Human Genome Project to the US and other governments by exploiting this genetic determinist myth: "We used to think our fate was written in the stars. Now we know it is written in our genes."

But when the human genome sequence was announced in 2001, private entrepreneur gene sequencer Craig Venter admitted that the genetic determinist myth could no longer be sustained: "We simply do not have enough genes for this idea of biological determinism to be right…The wonderful diversity of the human species is not hard-wired in our genetic code. Our environments are critical." This sent the genomics stock market on a downward spiral from which it never recovered.

In January 2002, Venter was sacked from the company Celera he created to sequence the human genome. Since then, genomics companies have rapidly gone out of business or switched directions to concentrate on ‘drug discovery’, to little avail. Celera reported a net loss of $19.4 million for the quarter ending December 31, 2004, considerably worse than the loss of $13.6 million the same quarter last year.

Venter told Business Week: "Biotech investors bought into the notion …that one gene leads to one protein and that equals £1 billion. Everyone thought there was a direct linear relationship between the genes and the breakthroughs. It was bio-babble. In reality, the genes are just the tip of the iceberg."

He also said, "companies see treating chronic disease as good for business. Instead of curing diabetes, for example, they want to treat it."

"Patients are a bankable asset"

Back in 2000, the Guardian newspaper carried an article on its financial page headlined, "Gene hunters say patients are a bankable asset". A California start-up company DNA Sciences set up a website to recruit DNA donors to help find genes that cause diseases. The company had James Watson as director and James Clark, founder of Netscape as an investor. It hoped to get 50 000 to 100 000 people to donate their DNA by appealing to their altruism. That company went bankrupt in April 2003, and was bought by Genaissance Pharmaceutical Inc. for a mere £1.35million in cash.

The hype on genomics started with the controversial takeover of the DNA database and health records of Iceland’s entire population by the private company DeCode Genetics in 1999. Thousands of Icelanders fell victim to the hype and invested millions. At their peak in 2001, shares were changing hands for $65. By the end of 2002, the shares listed on the Nasdaq index in New York had slumped to about $2.

I had warned against investing further in human genome research in 2000, as it had all the signs of being a "a scientific and financial black hole". A year later, I called the human genome a "big white elephant", a useless idol that will bankrupt the nation, robbing the public of investments that can really deliver the health of the nation.

But the desperate UK government went ahead with its DNA Biobank in 2002, funded so far at £62 million, to amass DNA and medical records from 500 000 volunteers aged between 45-69, to help researchers "unravel the origins" of important diseases such as heart disease, cancer diabetes and Alzheimer’s.

Critical voices

In March 2003, the highly influential House of Commons Select Committee on Science and Technology criticised the Biobank project as "politically driven"; and that the Medical Research Council leading the project had not adequately consulted the scientific community ("Parliament faults Research Council & DNA biobank", SiS 18).

Then, Sydney Brenner, who shared the 2002 Nobel Prize in physiology and medicine jointly with John Sulston and Robert Horvitz, told the BBC in September 2003 that more money should be invested in health education than in designing genetically tailored drugs [13]: "There are two kinds of health care. There’s taking care of the health of the public and there’s taking care of the financial health of the drug companies…you hear all these things about the human genome or personalised medicine and newer and safer drugs….maybe there is a new public health to be created. Maybe we should think of other ways of doing it." ("Nobel geneticist spurns genomics", SiS 20).

A year later, Sir Alec Jeffreys of Leicester University, inventor of DNA fingerprinting, warned that the costs of UK’s Biobank could spiral out of control, with "nothing useful" coming out of it. He said the money could be better spent on smaller, targeted projects to look at genetic and lifestyle factors in particular diseases.

To get "the full richness of genetic information" from all 500 000 people involves using millions of genetic markers, or trillions overall. Even if it costs a penny a time, the overall bill will come to £10 billion, said Jeffreys.

In the same month, UK’s Royal Society announced a year-long enquiry, headed by geneticist Sir David Weatherall, into the substance behind the hype of ‘designer’ personalised medicine, or pharmacogenetics.

Sir David said, "This study will look at whether pharmacogenetics, the designing of drug treatments based on a person’s genetic makeup, is a scientifically achievable aim…. Equally importantly it will look at whether healthcare systems in the UK and elsewhere have the resources to implement such technologies..."

Actually, critical voices have been raised from within the pharmaceutical industry almost as soon as the human genome map was announced. Writing in the journal Nature, Alan Roses of Glaxo Wellcome had made clear what the obstacles are to realising the goals of pharmacogenetics. It is very expensive to validate the new drug targets, so pharmaceutical companies prefer to make new variants of old drugs.

Roses distinguished ‘discovery genomics’ from ‘discovery genetics’. The former uses databases of DNA sequence information to identify genes and families of genes for possible drug targets; but these are not known to be associated with any disease, and worse, genes with similar sequences often have very different functions. The latter, ‘discovery genetics’ uses human population data, like UK’s DNA Biobank to identify disease-related susceptibility genes. But susceptibility genes are not drug targets, particularly because there are likely to be dozens if not hundreds associated with each common disease.

Designer drugs are not a scientifically achievable aim if one takes seriously what genetics science has been telling us.

What does genomics tell us?

According to the latest genome map statistics (Box 1), the classical (coding) gene sequences comprise a puny 1.5% of the genome, and the number of genes has dropped to its lowest, ever, between 20 000 and 25 000. The complexities are in the other parts of the genome, and downstream processes: the 97 to 98% of the transcripts that don’t code for proteins, and proteins that are 100 to 1000 times more numerous than genes due to alternative initiation of transcription, alternative splicing, trans-splicing, RNA-editing, and post-translational modifications (see later).

To deal with the ever expanding complexities, "systems biology" has been invented ("No system in systems biology", SiS21) that effectively promises not just to map, but to exhaustively amass data on the genome (the genetic text), the ‘transcriptome’ (all the RNA transcribed or copied), the ‘proteome’ (all the proteins translated), the ‘metabolome’ (all the metabolites due to chemical reactions), in the vain hope that the true meaning of life will emerge before the data deluge overflows the computer storage capacity of the entire planet and drowns us all.

A much touted technique for amassing data on the ‘transcriptome’ is the microarray of short DNA sequences immobilised on a glass plate, that enables researchers to compare and quantify the transcripts of thousands, if not tens of thousands of genes all at once (see "Gene gold turning to dust", this series). Such studies have been increasing exponentially since the mid 1990s. Unfortunately, most, if not all of them proved difficult to reproduce, sometimes even within the same laboratory. Some scientists have described microarray studies as a "methodological wasteland". But the problems are much deeper. Short probes for specific genes will invariably give inconsistent or contradictory results on account of processes such as alternative splicing that shuffles coding regions of the same or different genes and RNA editing that changes them beyond recognition from their genomic counterparts. Considering that gene transcripts are only 2 to 3% of the transcriptome, no serious scientist could really think it possible, or useful to map all of the transcripts.

Given these insurmountable problems of RNA complexity, it is perhaps foolish to consider tackling the ‘proteome’, which may contain millions or tens of millions of different proteins [24]. Several studies have already shown that there is a poor correlation between mRNA and protein on account of further post-transcriptional control of protein translation, and post-translational modification of proteins and protein degradation. Recent estimates suggest that there are more than 200 types of protein modification, and 5 to 10% of mammalian genes code for proteins that modify other proteins.

But it is the ‘fluidity’ of the genome that ultimately defeats the purpose of the exercise.

What the fluid genome tells us about health and disease…

The old genetics based on the Central Dogma supposes that the genetic text is written once and for all, and is transcribed and translated with fidelity. (This has usually been associated with hard-line genetic determinism; although Crick himself may have denied this in an apologia written later, where he said: "The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid.")

In contrast, the ‘fluid genome’ of the new genetics that has emerged since the early 1980s says that the genome and its genes are in constant conversation with the environment that changes not only how the genetic text is translated from moment to moment, but reinterpreted and rewritten in the light of experience. Furthermore, multiple tangled paths lead from the genetic text to final translation and back to the text (see "Life after the Central Dogma" series, SiS24).

Chemical markings on the DNA and proteins binding to the DNA in the chromosomes determine patterns of gene expression, i.e., which bits of the genetic text are actually read. That is very much influenced by experience. For example, the mother’s diet and stress – from assisted reproductive technologies - can affect patterns of gene expression in the embryo and foetus, which determines its health prospects as adults, in terms of susceptibility to a range of disease including cancer, stroke, diabetes, schizophrenia, manic depression ("What’s wrong with assisted reproductive technologies", SiS 20).

Researchers have even found genes that are marked for life in rat pups, strictly by how their mothers care for them during their first week of life after birth (see "Caring mothers reduce stress for life", SiS 24). It leaves one in no doubt that the environment is giving the instruction on which genes to turn on or off.

Only a few years ago, people were referring to the 98% to 99% of the genome that doesn’t code for proteins as "junk DNA". Not any more. The genome has a definite ‘architecture’ that holds up beneath the fluidity. There is a high degree of non-randomness in the parts of the genome that undergo change. While some parts are hypermutable, certain families of sequences are ‘homogenized’ to be nearly identical ("How to keep in concert" SiS 24), while still others are ‘ultraconservative’ in that they have remained absolutely unchanged in hundreds of millions of years of evolution ("Are ultraconserved elements indispensable?" SiS 24). Geneticists have speculated that the ultraconserved elements must have been under severe ‘selection pressure’. But when they chopped out large blocks of them from transgenic mice, those mice managed happily without them.

And when cells get into a tight corner metabolically speaking, there may even be genes that mutate to get them out of it ("To mutate or not to mutate" SiS 24).

There were early indications that the "junk DNA" may conceal a treasure trove of DNA sequences that are involved in coordinating the expression of suites of genes that have to act together to carry out complex functions ("Molecular genetic engineers in junk DNA?", SiS 19). Little did geneticists suspect that most of the action is not carried out by proteins, but by numerous species of RNA ‘interfering’ at all levels of the ‘readout’ of genetic information ( "Subverting the genetic text", SiS 24).

In what looks like a vast underworld of heresy to the Central Dogma, RNA agents decide which bits of text to copy, which copies to destroy, delete and splice together, which copies to transform into a totally different message and finally, which resulting message - that may bear little resemblance to the original text - gets translated into protein. RNAs even seem to decide which parts of the sacred text to rewrite or corrupt.

And this underworld is huge. Remember that at least half of the genome is transcribed, and around 97 – 98% of the transcripts of the human genome are non-protein-coding and potentially interfering RNAs.

Which is why genomics won’t deliver the health of nations

To sum up, conventional gene sequences that are translated into protein are just the tiny tips of huge mountains of concealed complexity beneath. Most of the action is in the 98.5 to 99% non-gene DNA and non-coding transcripts. There are well-known interactions between genes, dozens, possibly hundreds of transcription factors control the expression of overlapping sets of genes, that feed forward and feedback on one another, not to mention all the fluid genome processes that mark, convert or mutate genes in non-random ways.

There is no stable reference point to pin down an individual’s genome, transcriptome or proteome during his or her lifetime. Hunting for susceptibility genes or markers is like trawling for disappearing needles in an ever-shifting haystack.

And in stark contrast to the subtle, elusive effects of susceptibility genes, environmental influences swamp out even large genetic differences. The ‘obesity epidemic’ is a case in point. The majority of Europeans, Americans, Asians, Africans, Australians, New Zealanders, whatever, become overweight when they eat too much junk food and exercise too little. They also get cancers from radioactive wastes, pesticides and other industrial pollutants.

The DNA BioBank is a phenomenal waste of financial and intellectual resources (Box 2), and a massive distraction from addressing the real causes of ill health.

New evidence shows that toxic agents in the environment scramble genome sequences, and that those scrambled sequences may be linked to a range of chronic illnesses such Gulf War Syndrome, chronic fatigue syndrome, autoimmune diseases and leukaemia ( "Health and the fluid genome" series, SiS 19).

To keep our fluid genome constant and healthy, we need a balanced ecosystem free from pollutants, we need to move away from industrial monoculture to a biodiverse, sustainable agriculture that provides a nutritious diet to overcome both macronutrient and micronutrient deficiencies that compromise our physical and mental health, and to promote our natural immunity against infectious diseases including AIDS. These are infinitely more affordable measures that will benefit everyone, rich or poor.

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